Topical treatment or prevention of ocular infections

ABSTRACT

The topical application of an azalide antibiotic such as azithromycin to the eye is useful in treating or preventing ocular infections. In one embodiment, the azalide antibiotic is supplied to the eye in a depot for sustained release. A more convenient dosing regimen can also be provided by the use of an appropriate depot. Furthermore, a composition containing a combination of medicaments is also provided.

This application is a continuation of application Ser. No. 09/346,923,filed Jul. 2, 1999 now U.S. Pat. No. 6,239,113, which is acontinuation-in-part of prior U.S. patent application Ser. No.09/282,165, filed Mar. 31, 1999, now abandoned each of which is hereinincorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a method for treating or preventinginfections in the eye and to compositions useful therein.

2. Description of the Related Arts

The eye is susceptible to bacterial and parasitic infections arisingfrom both traumatic and non-traumatic related events. Infections are aconcern after ocular surgery and precautions are correspondingly takento prevent the onset of infection. However, even without the invasivetrauma of a surgical procedure, infections in the eyelids, conjunctiva,cornea, and other ocular tissues can arise.

Treating infections in ocular tissues can be challenging and/orproblematic because of the difficulty in delivering an antibiotic to theaffected tissue. In general, ocular infections are treated by localinjection, systemic administration, or topical application of anantibiotic. The route of administration depends on the antibioticselected, the location of the infection and the type of infection.

The simple and direct approach of topically applying the antibiotic tothe exterior of the eye has several benefits, including the avoidance ofside effects and the reduced chance of developing resistant strains ofbacteria as compared to systemic administration. However, for a varietyof reasons, many antibiotics are not amenable or suitable for topicalapplication to the eye.

For example, in order for a topical application to be effective, theantibiotic must be able to penetrate the desired tissue. This mayinclude penetrating the conjunctiva and the cornea. Also, thepenetration rate must be sufficient to impart an effective dose. Manydrugs do not possess a requisite penetration ability with regard to thetissues of the eye. It should be noted that the external layers of theeye are quite different from the tissues encountered in the stomach andintestinal tract. Thus, while a certain drug may be readily absorbed inthe intestines and introduced into the blood supply for systemicadministration, the same drug may be incapable of being absorbed by orpassing through the substantially avascular outer layers of theconjunctiva or cornea at a minimally acceptable therapeuticconcentration. The mechanism of transport or uptake of the drug isentirely different for topical administration than for oraladministration.

Another concern is that the antibiotic will be toxic to the eye. A toxicresponse includes redness, swelling and/or discharge. Toxicity isespecially problematic for topical administration because it is aconcentration dependent phenomenon. The concentration ratio between tearfluid and ocular tissue in topical administration is generally in therange of about 1:500 to 1:1000, due to the penetration gradient. Thus,while a drug may be non-toxic at the minimum effective concentration,the 500% to 1000% increase in concentration associated with topicaladministration may well induce a toxic response. Again, the fact thatoral or systemic administration shows the drug to be compatible withocular tissue does not predict or address the toxicity issue associatedwith topical administration.

A further potential unsuitability of an antibiotic is the practicalityof topical administration by the patient. Assuming that sufficientlyhigh concentrations of the antibiotic can be used to achieve aneffective dose within the target tissue without a toxic response, theapplication may nonetheless be irritating. An irritation responseincludes temporary burning, stinging and/or watering of the eye. Beyondwhether the increased watering of the eyes washes away so much of theantibiotic composition that an effective dose is prevented, the patientmay simply be resistant to complying with the dosage regimen because ofthe irritation. By failing to comply with the dosing regimen, thetreatment efficacy is reduced or eliminated.

Some antibiotics have been found to sufficiently meet the aboverequirements so as to be applicable to topical administration. Examplesof antibiotics that are reported to be useful in ocular topicaladministration include tobramycin, gentamycin, fluoroquinolonederivatives including norfloxacin, ofloxacin, and ciprofloxacin,naphthyridine, tetracyclines, and erythromycin. However, the dosing ofthe known topical antibiotics is usually an extensive and inconvenientregimen. Applying drops every 2 hours for the first two days and every 4hours for the next several days is a common dosing regimen for aqueoussolutions to treat ocular infections. But, such an extensive dosingregimen is inconvenient and obtaining patient compliance can bedifficult. Of course, the greater the non-compliance with the regimen,the less effective the treatment.

It would be beneficial to find additional antibiotics that are capableof topical application in treating the eye. It would be furtherdesirable to provide a topical formulation that is effective against abroad spectrum of bacteria and that can be administered in a lessextensive regimen.

SUMMARY OF THE INVENTION

The present invention relates to a process for treating an eye thatcomprises topically applying an azalide antibiotic to an eye in anamount effective to treat or prevent infection in a tissue of the eye.Applicants have discovered that azalide antibiotics are suitable fortopical administration to the eye. A preferred azalide antibiotic isazithromycin.

A preferred form of the invention involves forming or supplying a depotof the azalide antibiotic in contact with the eye for a sufficientlength of time to allow a minimum inhibitory concentration (MIC) of theazalide antibiotic to diffuse into the cells of the targeted eyetissue(s). Once the MIC threshold has been surpassed, a therapeuticallyeffective concentration of the azalide antibiotic will remain in thetissue(s) for a considerable period of time due to its long half-life.Accordingly, an advantage of certain preferred forms of the presentinvention is a simplified dosing regimen. For example, one or twotopical applications may provide a sufficient tissue concentration thatan inhibitory concentration remains resident in the infected tissue forseveral days, i.e. 4-12 days. Thus, a complete treatment regimen mayinvolve only one or two topical applications.

The invention also relates to a topical ophthalmic compositioncontaining an azalide antibiotic. In one embodiment, the ophthalmiccomposition is a sustained release composition comprised of an aqueoussuspension of the azalide antibiotic and a polymer suspending agent.

DETAILED DESCRIPTION OF THE INVENTION

Azalides are a known subclass of macrolide antibiotics. Occasionally,the literature has also referred to these compounds as azolides, and thetwo spellings should be taken as having the same meaning. For thepresent invention and as used in this specification, an “azalideantibiotic” means a derivitized erythromycin A structure having anitrogen atom inserted into the lactone ring. Additional variations fromthe erythromycin structure are also embraced within the term “azalideantibiotic.” Such additional variations include the conversion of ahydroxyl group to an alkoxy group, especially methoxy (so-called“O-methylated” forms), for example at the 6 and/or 12 position. Suchcompounds are described in U.S. Pat. No. 5,250,518, the entire contentsof which are incorporated herein by reference. Other variations relateto derivatives of the sugar moieties, for example, 3″ desmethoxyderivatives and the formation of oxo or oxime groups on the sugar ringsuch as at the 4″ position as described in U.S. Pat. No. 5,441,939, theentire contents of which are incorporated herein by reference. Thispatent also teaches that the adjacent hydroxyl groups at the 11 and 12position of the lactone ring can be replaced with a single carbonate orthiocarbonate group. In short, an azalide antibiotic for purposes of thepresent invention is any derivative of the erythromycin structure thatcontains a 15-member lactone ring having a ring nitrogen, preferably atthe 9 position, and a sugar group attached via a glycosidic bond to thelactone ring at the 5 position and at the 3 position, and which stillexhibits bacteriostatic or bactericidal activity.

Preferred azalide antibiotics are represented by formula (I) andpharmaceutically acceptable salts thereof.

R¹ and R² each independently represent a hydrogen atom or a methylgroup. Preferably at least one of R¹ and R² is a hydrogen atom.Azithromycin, the common name forN-methyl-11-aza-10-deoxo-10-dihydroerythromycin, corresponds to thecompound of formula (I) where both R¹ and R² are a hydrogen atom.Azithromycin was disclosed in U.S. Pat. Nos. 4,474,768 and 4,517,359,the entire contents of each patent being incorporated herein byreference, and is the most preferred azalide antibiotic. In particular,the dihydride form of azithromycin is especially contemplated for use inthe present invention, although other forms are also suitable.

Azithromycin has been used as an oral antibiotic and is sold worldwideunder the brand name Zithromax® by Pfizer Inc. Azithromycin is a broadspectrum antibiotic that is generally more effective in vitro thanerythromycin. Moreover, because azithromycin is an azalide and thus hasa ring nitrogen atom, it exhibits improved acid-stability, half-life,and cellular uptake in comparison to erythromycin. The high uptake andretention of azithromycin into cells, including phagocytic blood cells,allows the systemically administered azithromycin to be nonethelesspreferentially delivered to the site of the infection. The mechanism isbelieved to be as follows. The ingested azithromycin is absorbed throughthe intestine into the blood stream from which it enters most cells ofthe body including, inter alia, the white blood cells. In response to aninfection within the body, white blood cells, including those containingazithromycin, are attracted to the infectious site. When the white bloodcells die, the azithromycin is released. As more and more white bloodcells arrive at the infectious site and die, the concentration ofazithromycin in the surrounding tissue increases, eventually surpassingthe MIC. Once at the infectious site, the azithromycin remains in thetissue for a prolonged period of time, due to its long half-life, suchthat an effective concentration of azithromycin is present at theinfected site for many days after cessation of administration.

Although azithromycin can reach many of the tissues and fluids of theeye by oral administration, it has now been discovered that azalideantibiotics in general and azithromycin in particular are amenable totopical administration on the eye. The azalide antibiotic can besupplied to the eye surface in a variety of ways, including as anaqueous ophthalmic solution or suspension, as an ophthalmic ointment,and as an ocular insert, but application is not limited thereto. Anytechnique and ocular dosage form that supplies an azalide antibiotic tothe external eye surface is included within the notion of “topicallyapplying.” Although the external surface of the eye is typically theouter layer of the conjunctiva, it is possible that the sclera, corneaor other ocular tissue could be exposed such as by rotation of the eyeor by surgical procedure and thus be an external surface.

The amount of azalide antibiotic topically supplied is effective totreat or prevent infection in a tissue of the eye. This means that theconditions of application result in a retarding or suppression of theinfection. Typically at least about MIC₅₀ for the targeted bacteria orparasite is delivered to the ocular tissue by the topical application ofan effective amount. More concretely, the concentration within theocular tissue is desired to be at least about 0.25 μg/g, preferably atleast 1 μg/g, and more preferably at least 10 μg/g. The amount ofazalide actually supplied to the external eye surface will almost alwaysbe much higher than the tissue concentration. This reflects thepenetration hold up of the azalide antibiotic by the outer tissue layersof the eye and that penetration is to some extent concentration driven.Thus, supplying greater amounts to the exterior will drive moreantibiotic into the tissues.

Where a series of applications are used in the dosing regimen, it ispossible that one or more of the earlier applications will not achievean effective concentration in the ocular tissue, but that a laterapplication in the regimen will achieve an effective concentration. Thisis contemplated as being within the scope of topically applying anazalide antibiotic in an effective amount. However, generally a singleapplication, such as consisting of one or two drops, provides atherapeutically effective concentration (e.g. one that retards orsuppresses the infection) of the azalide antibiotic within a tissue ofthe eye. Indeed, although dependent on the amount and form of theophthalmic composition, a single application will typically provide atherapeutically effective amount of the azalide antibiotic within atissue of the eye for at least 8, preferably 12, and more preferably atleast 18 hours.

The topical application of an azalide antibiotic can be used to treat orprevent a variety of conditions associated with ocular infection. Forexample, conditions of the lids including blepharitis,blepharconjunctivies, meibomianitis, acute or chronic hordeolum,chalazion, dacryocystitis, dacryoadenities, and acne rosacea; conditionsof the conjunctiva including conjunctivitis, ophthalmia neonatorum, andtrachoma; conditions of the cornea including co meal ulcers, superficialand interstitial keratitis, keratoconjunctivitis, foreign bodies, andpost operative infections; and conditions of the anterior chamber anduvea including endophthalmitis, infectious uveitis, and post operativeinfections, are a few of the tissues and conditions that can be treatedby topical application of an azalide antibiotic. The prevention ofinfection includes pre-operative treatment prior to surgery as well asother suspected infectious conditions or contact. Examples ofprophylaxis situations include treatment prior to surgical proceduressuch as blepharoplasty, removal of chalazia, tarsorrhapy, procedures forthe canualiculi and lacrimal drainage system and other operativeprocedures involving the lids and lacrimal apparatus; conjunctivalsurgery including removal of ptyregia, pingueculae and tumors,conjunctival transplantation, traumatic lesions such as cuts, burns andabrasions, and conjunctival flaps; corneal surgery including removal offoreign bodies, keratotomy, and comeal transplants; refractive surgeryincluding photorefractive procedures; glaucoma surgery includingfiltering blebs; paracentesis of the anterior chamber; iridectomy;cataract surgery; retinal surgery; and procedures involving theextra-ocular muscles. The prevention of ophthalmia neonatorum is alsoincluded.

More generally, the azalide antibiotics can be used to treat or preventocular infections caused by a variety of bacteria or parasites,including but not limited to one or more of the following organisms:Staphylococcus including Staphylococcus aureus and Staphylococcusepidermidis; Streptococcus including Streptococcus pneumoniae andStreptococcus pyogenes as well as Streptococci of Groups C, F, and G andViridans group of Streptococci; Haemophilus influenza including biotypeIII (H. Aegyptius); Haemophilus ducreyi; Moraxella catarrhalis;Neisseria including Neisseria gonorrhoeae and Neisseria meningitidis;Chlamydia including Chlamydia trachomatis, Chlamydia psittaci, andChlamydia pneumoniae; Mycobacterium including Mycobacterium tuberculosisand Mycobacterium avium-intracellular complex as well as atypicalmycobacterium including M. marinum, M. fortuitm, and M. chelonae;Bordetella pertussis; Campylobacterjejuni; Legionella pneumophila;Bacteroides bivius; Clostridium perfringens; Peptostreptococcus species;Borrelia burgdorferi; Mycoplasma pneumoniae; Treponema pallidum;Ureaplasma urealyticum; toxoplasma; malaria; and nosema.

The azalide antibiotic is applied to the exterior surface of the eye,usually in an ophthalmically acceptable composition which comprises anophthalmically acceptable carrier and the azalide antibiotic. The“ophthalmically acceptable carrier” is used in a broad sense andincludes any material or composition that can contain and release theazalide antibiotic and that is compatible with the eye. Typically theophthalmically acceptable carrier is water or an aqueous solution orsuspension, but also includes oils such as those used to make ointmentsand polymer matrices such as used in ocular inserts. Generally, azalideantibiotics are poorly soluble in water. However, water solubility isimproved if converted to a salt form. For example, azithromycindihydrochloride has good water solubility. Accordingly, an aqueoussolution of an azalide antibiotic can be formed and used for topicalapplication. But, more typically, an aqueous suspension is formed of thepoorly soluble or insoluble azalide antibiotic. Ointments and soliddosage forms can also be used as delivery compositions as are well knownin the art. The concentration of azalide antibiotic present in theophthalmic composition depends upon the dosage form, the release rate,the dosing regimen, and the location and type of infection. Generallyspeaking, the concentration is from about 0.01 to 2%, more typically 0.1to 1%, for fluid compositions and 0.5 to 50% for solid dosage forms,however, the compositions are not limited thereto.

The fluid ophthalmic compositions of the present invention, includingboth ointments and suspensions, have a viscosity that is suited for theselected route of administration. A viscosity in the range of from about1,000 to 30,000 centipoise is useful for a drop. About 30,000 to about100,000 centipoise is an advantageous viscosity range for ophthalmicadministration in ribbon form. The viscosity can be controlled in manyways known to the worker skilled in the art.

The ophthalmic compositions may contain one or more of the following:surfactants, adjuvants including additional medicaments, buffers,antioxidants, tonicity adjusters, preservatives, thickeners or viscositymodifiers, and the like. Additives in the formulation may desirablyinclude sodium chloride, EDTA (disodium edetate), and/or BAK(benzalkonium chloride), sorbic acid, methyl paraben, propyl paraben,chlorhexidine, and sodium perborate.

A further aspect of the present invention involves the above-mentioneduse of additional medicaments in combination with the azalideantibiotic. A composition comprising an azalide antibiotic, anadditional medicament, and an ophthalmically acceptable carrier canadvantageously simplify administration and allow for treating orpreventing multiple conditions or symptoms simultaneously. The“additional medicaments,” which can be present in any of the ophthalmiccompositional forms described herein including fluid and solid forms,are pharmaceutically active compounds having efficacy in ocularapplication and which are compatible with an azalide antibiotic and withthe eye. Typically, the additional medicaments include otherantibiotics, antivirals, antifungals, anesthetics, anti-inflammatoryagents including steroidal and non-steroidal anti-inflammatories, andanti-allergic agents. Examples of suitable medicaments includeaminoglycosides such as amikacin, gentamycin, tobramycin, streptomycin,netilmycin, and kanamycin; fluoroquinolones such as ciprofloxacin,norfloxacin, ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, andenoxacin; naphthyridine; sulfonamides; polymyxin; chloramphenicol;neomycin; paramomomycin; colistimethate; bacitracin; vancomycin;tetracyclines; rifampin and its derivatives (“rifampins”); cycloserine;beta-lactams; cephalosporins; amphotericins; fluconazole; flucytosine;natamycin; miconazole; ketoconazole; corticosteroids; diclofenac;flurbiprofen; ketorolac; suprofen; comolyn; lodoxamide; levocabastin;naphazoling; antazoline; and pheniramimane. These other medicaments aregenerally present in a pharmaceutically effective amount as isunderstood by workers of ordinary skill in the art. These amounts aregenerally within the range of from about 0.01 to 5%, more typically 0.1to 2%, for fluid compositions and from 0.5 to 50% for solid dosageforms.

The aqueous ophthalmic compositions (solutions or suspensions) for usein the present invention use water which has no physiologically orophthalmically harmful constituents. Typically purified or deionizedwater is used. The pH is adjusted by adding any physiologically andophthalmically acceptable pH adjusting acids, bases or buffers to withinthe range of about 5.0 to 8.5. Examples of acids include acetic, boric,citric, lactic, phosphoric, hydrochloric, and the like, and examples ofbases include sodium hydroxide, sodium phosphate, sodium borate, sodiumcitrate, sodium acetate, sodium lactate, tromethamine, THAM(trishydroxymethylamino-methane), and the like. Salts and buffersinclude citrate/dextrose, sodium bicarbonate, ammonium chloride andmixtures of the aforementioned acids and bases.

The osmotic pressure (π) of the aqueous ophthalmic composition isgenerally from about 10 milliosmolar (mOsM) to about 400 mOsM, morepreferably from 260 to 340 mOsM. If necessary, the osmotic pressure canbeadjusted by using appropriate amounts of physiologically andophthalmically acceptable salts or excipients. Sodium chloride ispreferred to approximate physiologic fluid, and amounts of sodiumchloride ranging from about 0.01% to about 1% by weight, and preferablyfrom about 0.05% to about 0.45% by weight, based on the total weight ofthe composition, are typically used. Equivalent amounts of one or moresalts made up of cations such as potassium, ammonium and the like andanions such as chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate, bisulfate, sodium bisulfate, ammoniumsulfate, and the like can also be used in addition to or instead ofsodium chloride to achieve osmolalities within the above-stated range.Similarly, a sugar such as mannitol, dextrose, sorbitol, glucose and thelike can also be used to adjust osmolality.

A preferred form of the present invention provides achieving asufficiently high tissue concentration with a minimum of doses so that asimple dosing regimen can be used to treat or prevent bacterial orparasitic infections. To this end, a preferred technique involvesforming or supplying a depot of azalide antibiotic in contact with theexternal surface of the eye. A depot refers to a source of azalideantibiotic that is not rapidly removed by tears or other eye clearancemechanisms. This allows for continued, sustained high concentrations ofazalide antibiotic to be present in the fluid on the external surface ofthe eye by a single application. In general, it is believed thatabsorption and penetration are dependent on both the dissolved drugconcentration and the contact duration of the external tissue with thedrug-containing fluid. As the drug is removed by clearance of the ocularfluid and/or absorption into the eye tissue, more drug is provided, e.g.dissolved, into the replenished ocular fluid from the depot.

Accordingly, the use of a depot more easily facilitates loading of theocular tissue in view of the typically slow and low penetration rate ofthe generally water-insoluble/poorly soluble azalide antibiotics. Thedepot can effectively slowly “pump” the azalide antibiotic into theocular tissue. As the azalide antibiotic penetrates the ocular tissue itis accumulated therein and not readily removed due to its longhalf-life. As more azalide antibiotic is “pumped” in, the tissueconcentration increases and the minimum inhibitory concentrationthreshold is eventually reached and/or exceeded, thereby loading theocular tissue with azalide antibiotic. By significantly exceeding theMIC₅₀, more preferably the MIC₉₀ level, provided the toxicity limit isnot exceeded, a therapeutically effective concentration will remainactive in the tissue for an extended period of time due to the lowclearance rate of the azalide antibiotic from the tissue. Thus,depending on the depot, one or two applications may provide a completedosing regimen. Indeed, such a simple dosing regimen may provide a 6 to14 day treatment concentration within the ocular tissue. A preferreddosing regimen involves one to two doses per day over a one to three dayperiod, more preferably one or two doses in a single day, to provide invivo at least a 6 day treatment and more typically a 6 to 14 daytreatment.

A depot can take a variety of forms so long as the azalide antibioticcan be provided in sufficient concentration levels therein and isreleasable therefrom and that the depot is not readily removed from theeye. A depot generally remains for at least about 30 minutes afteradministration, preferably at least 2 hours and more preferably at least4 hours. The term “remains” means that neither the depot composition northe azalide antibiotic is exhausted or cleared from the surface of theeye prior to the indicated time. In some embodiments, the depot canremain for up to eight hours or more. Typical ophthalmic depot formsinclude aqueous polymeric suspensions, ointments, and solid inserts.Polymeric suspensions are the most preferred form for the presentinvention and will be discussed subsequently.

Ointments are well known ophthalmic compositions and are essentially anoil-based delivery vehicle. Typical ointments use a petroleum and/orlanolin base to which is added the active ingredient, usually as 0.1 to2%, and excipients. Common bases include mineral oil, petrolatum andcombinations thereof, but oil bases are not limited thereto. Sinceazalide antibiotics are frequently only sparingly soluble in water, anointment is a logical form of administration. An ointment is usuallyapplied as a ribbon onto the lower eyelid. The disadvantage of ointmentsis that they are difficult to administer, are messy, anduncomfortable/inconvenient to the patient; i.e. temporarily blurredvision is common.

Inserts are another well known ophthalmic dosage form and are comprisedof a matrix containing the active ingredient. The matrix is typically apolymer and the active ingredient is generally dispersed therein orbonded to the polymer matrix. The active ingredient is slowly releasedfrom the matrix through dissolution or hydrolysis of the covalent bond,etc. In some embodiments, the polymer is bioerodible (soluble) and thedissolution rate thereof can control the release rate of the activeingredient dispersed therein. In another form, the polymer matrix is abiodegradable polymer that breaks down such as by hydrolysis to therebyrelease the active ingredient bonded thereto or dispersed therein. Thematrix and active ingredient can be surrounded with a polymeric coatingsuch as in the sandwich structure of matrix/matrix+active/matrix, tofurther control release as is well known in the art. The kinds ofpolymers suitable for use as a matrix are well known in the art. Theazalide antibiotic can be dispersed into the matrix material ordispersed amongst the monomer composition used to make the matrixmaterial prior to polymerization. The amount of azalide antibiotic isgenerally from about 0.1 to 50%, more typically about 2 to 20%. Theinsert can be placed, deperiding on the location and the mechanism usedto hold the insert in position, by either the patient or the doctor andis generally located under the upper eyelid. A variety of shapes andanchoring configurations, if any, are well known in the art. Preferablya biodegradable or bioerodible polymer matrix is used so that the spentinsert does not have to be removed. As the biodegradable or bioerodiblepolymer is degraded or dissolved, the trapped azalide antibiotic isreleased. Although inserts can provide long term release and hence onlya single application of the insert may be necessary, they are generallydifficult to insert and are uncomfortable to the patient.

The preferred form is an aqueous polymeric suspension. Here, at leastone of the azalide antibiotic or the polymeric suspending agent issuspended in an aqueous medium having the properties as described above.Typically the azalide antibiotic is in suspension although it ispossible for the azalide antibiotic to be in solution(water soluble) orboth in solution and in suspension in significant amounts generally noless than 5% in either phase (weak to moderate water solubility andrelatively high total concentrations). The polymeric suspending agent ispreferably a suspension (i.e. water insoluble and/or water swellable),although water soluble suspending agents are also suitable for use witha suspension of the azalide antibiotic. The suspending agent serves toprovide stability to the suspension and to increase the residence timeof the dosage form on the eye. It can also enhance the sustained releaseof the drug in terms of both longer release times and a more uniformrelease curve.

Examples of polymeric suspending agents include dextrans, polyethyleneglycols, polyvinylpyrolidone, polysaccharide gels, Gelrite®, cellulosicpolymers like hydroxypropyl methylcellulose, and carboxy-containingpolymers such as polymers or copolymers of acrylic acid, as well asother polymeric demulcents. A preferred polymeric suspending agent is awater swellable, water insoluble polymer, especially a crosslinkedcarboxy-containing polymer.

Crosslinked carboxy-containing polymers used in practicing thisinvention are, in general, well known in the art. In a preferredembodiment such polymers may be prepared from at least about 90% andpreferably from about 95% to about 99.9% by weight, based on the totalweight of monomers present, of one or more carboxy-containingmonoethylenically unsaturated monomers (also occasionally referred toherein as carboxy-vinyl polymers). Acrylic acid is the preferredcarboxy-containing monoethylenically unsaturated monomer, but otherunsaturated, polymerizable carboxy-containing monomers, such asmethacrylic acid, ethacrylic acid, β-methylacrylic acid (crotonic acid),cis-α-methylcrotonic acid (angelic acid), trans-α-methylcrotonic acid(tiglic acid), α-butylcrotonic acid, α-phenylacrylic acid,α-benzylacrylic acid, α-cyclohexylacrylic acid, β-phenylacrylic acid(cinnamic acid), coumaric acid (o-hydroxycinnamic acid), umbellic acid(p-hydroxycoumaric acid), and the like can be used in addition to orinstead of acrylic acid.

Such polymers may be crosslinked by a polyfunctional crosslinking agent,preferably a difunctional crosslinking agent. The amount of crosslinkingshould be sufficient to form insoluble polymer particles, but not sogreat as to unduly interfere with sustained release of the azalideantibiotic. Typically the polymers are only lightly crosslinked.Preferably the crosslinking agent is contained in an amount of fromabout 0.01% to about 5%, preferably from about 0.1% to about 5.0%, andmore preferably from about 0.2% to about 1%, based on the total weightof monomers present. Included among such crosslinking agents arenon-polyalkenyl polyether difunctional crosslinking monomers such asdivinyl glycol; 2,3-dihydroxyhexa-1,5-diene; 2,5-dimethyl-1,5-hexadiene;divinylbenzene; N,N-diallylacrylamide; N,N-diallymethacrylamide and thelike. Also included are polyalkenyl polyether crosslinking agentscontaining two or more alkenyl ether groupings per molecule, preferablyalkenyl ether groupings containing terminal H₂C═C<groups, prepared byetherifying a polyhydric alcohol containing at least four carbon atomsand at least three hydroxyl groups with an alkenyl halide such as allylbromide or the like, e.g., polyallyl sucrose, polyallyl pentaerythritol,or the like; see, e.g., Brown U.S. Pat. No. 2,798,053, the entirecontents of which are incorporated herein by reference. Diolefinicnon-hydrophilic macromeric crosslinking agents having molecular weightsof from about 400 to about 8,000, such as insoluble di-acrylates andpolyacrylates and methacrylates of diols and polyols,diisocyanate-hydroxyalkyl acrylate or methacrylate reaction products ofisocyanate terminated prepolymers derived from polyester diols,polyether diols or polysiloxane diols with hydroxyalkylmethacrylates,and the like, can also be used as the crosslinking agents; see, e.g.,Mueller et al. U.S. Pat. Nos. 4,192,827 and 4,136,250, the entirecontents of each Patent being incorporated herein by reference.

The crosslinked carboxy-vinyl polymers may be made from a carboxy-vinylmonomer or monomers as the sole monoethylenically unsaturated monomerpresent, together with a crosslinking agent or agents. Preferably thepolymers are ones in which up to about 40%, and preferably from about 0%to about 20% by weight, of the carboxy-containing monoethylenicallyunsaturated monomer or monomers has been replaced by one or morenon-carboxyl-containing monoethylenically unsaturated monomer ormonomers containing only physiologically and ophthalmically innocuoussubstituents, including acrylic and methacrylic acid esters such asmethyl methacrylate, ethyl acrylate, butyl acrylate,2-ethylhexylacrylate, octyl methacrylate, 2-hydroxyethyl-methacrylate,3-hydroxypropylacrylate, and the like, vinyl acetate,N-vinylpyrrolidone, and the like; see Mueller et al. U.S. Pat. No.4,548,990, the entire contents of which are incorporated herein byreference, for a more extensive listing of such additionalmonoethylenically unsaturated monomers.

Particularly preferred polymers are lightly crosslinked acrylic acidpolymers wherein the crosslinking monomer is 2,3-dihydroxyhexa-1,5-dieneor 2,3-dimethylhexa-1,5-diene. Preferred commercially available polymersinclude polycarbophil (Noveon AA-1) and Carbopol®. Most preferably, acarboxy-containing polymer system known by the tradename DuraSite®,containing polycarbophil, which is a sustained release topicalophthalmic delivery system that releases the drug at a controlled rate,is used in the aqueous polymeric suspension composition of the presentinvention.

The crosslinked carboxy-vinyl polymers used in practicing this inventionare preferably prepared by suspension or emulsion polymerizing themonomers, using conventional free radical polymerization catalysts, to adry particle size of not more than about 50 μm in equivalent sphericaldiameter; e.g., to provide dry polymer particles ranging in size fromabout 1 to about 30 μm, and preferably from about 3 to about 20 μm, inequivalent spherical diameter. Using polymer particles that wereobtained by mechanically milling larger polymer particles to this sizeis preferably avoided. In general, such polymers will have a molecularweight which has been variously reported as being from about 250,000 toabout 4,000,000, and from 3,000,000,000 to 4,000,000,000.

In the most preferred embodiment of the invention, the particles ofcrosslinked carboxy-vinyl polymer are monodisperse, meaning that theyhave a particle size distribution such that at least 80% of theparticles fall within a 10 μm band of major particle size distribution.More preferably, at least 90% and most preferably at least 95%, of theparticles fall within a 10 μm band of major particle size distribution.Also, a monodisperse particle size means that there is no more than 20%,preferably no more than 10%, and most preferably no more than 5%particles of a size below 1 μm. The use of a monodispersion of particleswill give maximum viscosity and an increased eye residence time of theophthalmic medicament delivery system for a given particle size.Monodisperse particles having a particle size of 30 μm and below aremost preferred. Good particle packing is aided by a narrow particle sizedistribution.

The aqueous polymeric suspension normally contains 0.05 to 1%,preferably 0.1 to 0.5%, more preferably 0.1 to 0.5%, of the azalideantibiotic and 0.1 to 10%, preferably 0.5 to 6.5% of a polymericsuspending agent. In the case of the above described water insoluble,water-swellable crosslinked carboxy-vinyl polymer, a more preferredamount of the polymeric suspending agent is an amount ranging from 0.5to 2.0%, preferably from 0.5% to about 1.2%, and in certain embodimentsfrom 0.6 to 0.9%, based on the weight of the composition. Althoughreferred to in the singular, it should be understood that one or morespecies of polymeric suspending agent such as the crosslinkedcarboxy-containing polymer can be used with the total amount fallingwithin the stated ranges. In one preferred embodiment, the compositioncontains 0.6 to 0.8% of a polycarbophil such as NOVEON AA-1.

In one embodiment, the amount of insoluble lightly crosslinkedcarboxy-vinyl polymer particles, the pH, and the osmotic pressure can becorrelated with each other and with the degree of crosslinking to give acomposition having a viscosity in the range of from about 500 to about100,000 centipoise, and preferably from about 1,000 to about 30,000 orabout 1,000 to about 10,000 centipoise, as measured at room temperature(about 25° C.) using a Brookfield Digital LVT Viscometer equipped with anumber 25 spindle and a 13R small sample adapter at 12 rpm.Alternatively, when the viscosity is within the range of 500 to 3000centipoise, it may be determined by a Brookfield Model DV-11+, choosinga number cp-52 spindle at 6 rpm.

When water soluble polymers are used as the suspending agent, such ashydroxypropyl methylcellulose, the viscosity will typically be about 10to about 400 centipoise, more typically about 10 to about 200centipoises or about 10 to about 25 centipoise.

Aqueous polymeric suspensions of the present invention may be formulatedso that they retain the same or substantially the same viscosity in theeye that they had prior to administration to the eye. Alternatively,they may be formulated so that there is increased gelation upon contactwith tear fluid. For instance, when a formulation containing DuraSite®or other similar polyacrylic acid-type polymer is administered to theeye at a pH of less than about 6.7, the polymer will swell upon contactwith tear fluid since it has a higher pH (around 7). This gelation orincrease in gelation leads to entrapment of the suspended azalideantibiotic particles, thereby extending the residence time of thecomposition in the eye. The azalide antibiotic is released slowly as thesuspended particles dissolve over time. All these events eventually leadto increased patient comfort and increased azalide antibiotic contacttime with the eye tissues, thereby increasing the extent of drugabsorption and duration of action of the formulation in the eye.

The viscous gels that result from fluid eye drops typically haveresidence times in the eye ranging from about 2 to about 12 hours, e.g.,from about 3 to about 6 hours. The agents contained in these drugdelivery systems will be released from the gels at rates that depend onsuch factors as the drug itself and its physical form, the extent ofdrug loading and the pH of the system, as well as on any drug deliveryadjuvants, such as ion exchange resins compatible with the ocularsurface, which may also be present.

The compositions used to topically deliver the azalide antibiotic of thepresent invention can be prepared from known or readily availablematerials through the application of known techniques by workers ofordinary skill in the art without undue experimentation. The azalideantibiotics used in the present invention are commercially available orreadily obtained by a worker skilled in the art through known reactionstechniques. In particular, the azalide antibiotics can be formed fromerythromycin A, a naturally occurring compound formed during theculturing of a strain of Streptomyces erythreus. However, it is notrequired that the azalide antibiotic actually be formed fromerythromycin. The azalide antibiotic can be combined with the otheringredients in the chosen dosage form by conventional methods known inthe art.

The azalide antibiotic-containing composition is topically applied to aneye of a human or non-human animal, the latter including cows, sheep,horses, pigs, goats, rabbits, dogs, cats, and other mammals. Thecomposition can be applied as a liquid drop, ointment, a viscoussolution or gel, a ribbon or as a solid. The composition can betopically applied, without limitation, to the front of the eye, underthe upper eyelid, on the lower eyelid and in the cul-de-sac. Theapplication can be as a treatment of an infection in the eye or as apreventive such as prior to surgery.

All of the percentages recited herein refer to weight percent, unlessotherwise indicated. The following non-limiting examples serve toillustrate certain features of the present invention. The compositionsand amounts used for Examples 1-7 are summarized in Table 1 and forExamples 9-14 in Table 2.

Examples 1-2

Hydroxypropylmethyl cellulose, sodium chloride, edetate sodium (EDTA),BAK and surfactant are dissolved in a beaker containing approximately ⅓of the final weight of water and stirred for 10 minutes with an overheadstirred. The azithromycin is added and stirred to disperse for 30minutes. The solution is sterilized by autoclaving at 121° C. for 20minutes. Alternately, the azithromycin may be dry heat sterilized andadded by aseptic powder addition after sterilization. Mannitol,Poloxamer 407, and boric acid are dissolved separately in approximately½ of the final weight of water and added by sterile filtration (0.22 μmfilter) and stirred for 10 minutes to form a mixture. The mixture isadjusted to desired pH with 10N sodium hydroxide while stirring, broughtto a final weight with water by sterile filtration and asepticallyfilled into multi-dose containers.

Examples 3-6

Noveon AA-1 is slowly dispersed into a beaker containing approximately ⅓of the final weight of water and stirred for 1.5 hrs. with an overheadstirrer. Noveon AA-1 is an acrylic acid polymer available from B.F.Goodrich. Edetate sodium (EDTA), BAK, sodium chloride, and surfactantare then added to the polymer solution and stirred for 10 minutes aftereach addition. The polymer suspension is at a pH of about 3.0-3.5. Theazithromycin is added and stirred to disperse for 30 minutes. Themixture is sterilized by autoclaving at 121° C., for 20 minutes.Alternately, the azithromycin may be dry heat sterilized and added byaseptic powder addition after sterilization. Mannitol, and boric acid,or sodium perborate, Dequest, mannitol, and boric acid are dissolvedseparately in approximately ½ of the final weight of water, added to thepolymer mixture by sterile filtration (0.22 μm filter) and stirred for10 minutes. The mixture is adjusted to the desired pH with 10N sodiumhydroxide while stirring, brought to final weight with water by sterilefiltration and aseptically filled into multi-dose containers.

Example 7

Noveon AA-1 is slowly dispersed into a beaked containing approximately ½of the final weight of water and stirred for 1.5 hrs. With overheadstirrer. Noveon AA-1 is an acrylic acid polymer available from B.F.Goodrich. Edetate sodium (EDTA), Poloxamer 407, and sodium chloride arethen added to the polymer suspension and stirred for 10 minutes. Thepolymer suspension is at a pH of about 3.0-3.5. The azithromycin isadded and stirred to disperse for 30 minutes. The mixture is sterilizedby autoclaving at 121° C. for 20 minutes. Alternately, the azithromycinmay be dry heat sterilized and added by aseptic powder addition aftersterilization. Mannitol is dissolved in {fraction (1/10)} of the finalweight of water and sterile filtered (0.22 μm filter) in to the polymersuspension and stirred for 10 minutes. The mixture is adjusted todesired pH with 10N sodium hydroxide while stirring, brought to finalweight with water by sterile filtration and aseptically filled intounit-dose containers.

TABLE 1 Formulation Examples 1-7 1 2 3 4 Ingredient % % % % Azithromycin0.10 0.50 0.10 0.50 Hydroxypropyl 1.50 2.00 — — Cellulose Noveon AA-1 —— 0.80 0.80 Sodium Chloride 0.20 0.20 0.20 0.20 Mannitol 1.50 1.50 1.501.50 Edetate Disodium 0.10 0.10 0.10 0.10 Poloxamer 407 0.10 0.10 0.100.10 Benzalkonium Chloride 0.01 0.01 0.01 0.01 Sodium Perborate — — — —Dequest 2060S — — — — Boric Acid 0.50 0.50 0.50 0.50 Sodium Hydroxideq.s. to pH q.s. to pH q.s. to pH q.s. to pH 7 7 6 6 Water q.s. to 100q.s. to 100 q.s. to 100 q.s. to 100 5 6 7 Ingredient % % % Azithromycin0.50 0.50 0.10 Hydroxypropyl — — — Cellulose Noveon AA-1 0.80 0.80 0.80Sodium Chloride 0.20 0.20 0.30 Mannitol 1.50 1.50 1.50 Edetate Disodium0.10 0.10 Poloxamer 407 0.10 0.10 0.10 Benzalkonium Chloride — 0.01 —Sodium Perborate 0.10 — — Dequest 2060S 0.10 — — Boric Acid 0.50 0.50Sodium Hydroxide q.s. to pH q.s. to pH q.s. to pH 6 7 6 Water q.s. to100 q.s. to 100 q.s. to 100

Example 8

An azithromycin ointment is prepared by dissolving 0.3 grams ofazithromycin and 0.5 grams of chlorobutanol in a mixture containing 3.0grams mineral oil/96.2 grams white petrolatum by stirring in a 100 mlbeaker while heating sufficiently hot to dissolve both compounds. Themixture is sterile filtered through a 0.22 μm filter at a sufficienttemperature to be filtered and filled aseptically into sterileophthalmic ointment tubes.

Example 9-11

Hydroxypropylmethyl cellulose (HPMC), sodium chloride, edetate sodium(EDTA), and surfactant are dissolved in a beaker containingapproximately ⅓ of the final weight of water and stirred for 10 minuteswith an overhead stirrer. The mixture is sterilized by autoclaving at121° C., for 20 minutes. The azithromycin and steroid as indicated intable 2 are dry heat sterilized and added to the HPMC-containingsolution by aseptic powder addition. Mannitol, Poloxamer 407, BAK, andboric acid are dissolved separately in approximately ½ of the finalweight of water and added by sterile filtration (0.22 μm filter) andstirred for 10 minutes to form a mixture. The mixture is adjusted todesired pH with 10N sodium hydroxide while stirring, brought to a finalweight with water by sterile filtration, and aseptically filled intomulti-dose containers.

Examples 12-14

Noveon AA-1 is slowly dispersed into a beaker containing approximately ⅓of the final weight of water and stirred for 1.5 hrs. with an overheadstirrer. Noveon AA-1 is an acrylic acid polymer available from B.F.Goodrich. Edetate sodium (EDTA), sodium chloride, and surfactant arethen added to the polymer solution and stirred for 10 minutes after eachaddition. The polymer suspension is at a pH of about 3.0-3.5. Themixture is sterilized by autoclaving at 121° C. for 20 minutes. Theazithromycin and steroid as indicated in table 2 are dry heat sterilizedand added to the polymer suspension by aseptic powder addition. BAK,mannitol, and boric acid are dissolved separately in approximately ½ ofthe final weight of water, added to the polymer mixture by sterilefiltration (0.22 μm filter) and stirred for 10 minutes. The mixture isadjusted to the desired pH with 10N sodium hydroxide while stirring,brought to final weight with water and by sterile filtration andaseptically filled into multi-dose containers.

TABLE 2 Formulation Examples 9-14 9 10 11 12 13 14 Ingredient % % % % %% Azithromycin 0.10 0.10 0.10 0.10 0.10 0.10 Prednisolone 0.10 — — 0.10— — Acetate Fluoro- — 0.10 — — 0.10 — metholone Dexamethasone — — 0.10 —— 0.10 Hydroxypropyl 1.50 1.50 1.50 — — — methyl Cellulose Noveon AA-1 —— — 0.80 0.80 0.80 Sodium 0.20 0.20 0.20 0.20 0.20 0.20 ChlorideMannitol 1.50 1.50 1.50 1.50 1.50 1.50 Edetate 0.10 0.10 0.10 0.10 0.100.10 Disodium Poloxamer 407 0.10 0.10 0.10 0.10 0.10 0.10 Benzalkonium0.01 0.01 0.01 0.01 0.01 0.01 Chloride Boric Acid 0.50 0.50 0.50 0.500.50 0.50 Sodium q.s. to q.s. to q.s. to q.s. to q.s. to q.s. toHydroxide pH 7 pH 7 pH 7 pH 6 pH 6 pH 6 Water q.s. to q.s. to q.s. toq.s. to q.s. to q.s. to 100 100 100 100 100 100

The about discussion of this invention is directed primarily topreferred embodiments and practices thereof. It will be readily apparentto those skilled in the art that further changes and modifications inactual implementation of the concepts described herein can easily bemade or may be learned by practice of the invention, without departingfrom the spirit and scope of the invention as defined by the followingclaims.

We claim:
 1. A process for treating an eye, comprising: topicallyapplying an azalide antibiotic to an eye in an amount effective to treatinfection in a tissue of the eye, wherein said topically applyingcomprises supplying a depot of a composition containing said azalideantibiotic on the eye.
 2. The process according to claim 1, wherein saideye is suffering from at least one condition selected from the groupconsisting of conjunctivitis, ophthalmia neonatorum, trachoma, cornealulcers, keratitis, keratoconjunctivitis, endophthalmitis, infectiousuveitis and combinations thereof, and said amount of said azalideantibiotic is therapeutically effective to treat said condition.
 3. Theprocess according to claim 1, wherein said azalide antibiotic is acompound of formula (I):

wherein R¹ and R² each independently represent a hydrogen atom or methylgroup.
 4. The process according to claim 3, wherein said azalideantibiotic is azithromycin.
 5. The process according to claim 3, whereinsaid applying provides a therapeutically effective concentration ofazalide antibiotic within a tissue of the eye for at least 8 hours. 6.The process according to claim 5, wherein said applying provides atherapeutically effective concentration of azalide antibiotic within atissue of the eye for at least 12 hours.
 7. The process according toclaim 6, wherein said applying provides a therapeutically effectiveconcentration of azalide antibiotic within a tissue of the eye for atleast 18 hours.
 8. The process according to claim 1, wherein said depotis an aqueous polymeric suspension of said azalide antibiotic.
 9. Theprocess according to claim 8, wherein said aqueous polymeric suspensionfurther comprises an additional medicament.
 10. The process according toclaim 9, wherein said additional medicament is selected from the groupconsisting of amikacin, gentamycin, tobramycin, streptomycin,netilmycin, kanamycin ciprofloxacin, norfloxacin, ofloxacin,trovafloxacin, lomefloxacin, levofloxacin, enoxacin, sulfonamides,polymyxin, chloramphenicol, neomycin, paramomomycin, colistimethate,bacitracin, vancomycin, tetracyclines, rifampins, cycloserine,beta-lactams, cephalosporins, amphotericins, fluconazole, flucytosine,natamycin, miconazole, ketoconazole, corticosteroids, diclofenac,flurbiprofen, ketorolac, suprofen, comolyn, lodoxamide, levocabastin,naphazoling, antazoline, and. pheniramimane.
 11. The process accordingto claim 1, wherein said depot is a composition selected from the groupconsisting of an aqueous suspensions, ointments, and inserts.
 12. Theprocess according to claim 11, wherein said composition furthercomprises an additional medicament.
 13. The process according to claim12, wherein said additional medicament is selected from the groupconsisting of antibiotics, antivirals, antifungals, anesthetics,anti-inflammatory agents, and anti-allergic agents.
 14. The processaccording to claim 1, wherein said depot remains for at least 30 minutesafter administration.
 15. The process according to claim 14, whereinsaid depot remains for at least 4 hours after administration.
 16. Atopical ophthalmic composition comprising an aqueous polymericsuspension comprising water, 0.01% to 1.0% of an azalide antibiotic and0.1 to 10% of a polymeric suspending agent, wherein said topicalophthalmic composition has an osmotic pressure of from 10 to 400 mOsMand wherein said composition does not contain constituents that arephysiologically or ophthalmically harmful to the eye.
 17. Thecomposition according to claim 16, wherein said suspension furthercomprises an additional medicament selected from the group consisting ofantibiotics, antivirals, antifungals, anesthetics, anti-inflammatoryagents, and anti-allergic agents.
 18. The composition according to claim17, wherein said additional medicament is contained in the amount offrom 0.01 to 5.0%.
 19. The composition according to claim 17, whereinsaid additional medicament is selected from the group consisting ofamikacin, gentamycin, tobramycin, streptomycin, netilmycin, kanamycin,ciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin,levofloxacin, enoxacin, sulfonamides, polymyxin, chloramphenicol,neomycin, paramomomycin, colistimethate, bacitran, vancomycin,tetracyclines, rifampins, cycloserine, beta-lactams, cephalosporins,amphotericins, fluconazole, flucytosine, matamycin, miconazole,ketoconazole, corticosteroids, diclofenac, flurbiprofen, ketorolac,suprofen, comolyn, lodoxamide, levocabastin, naphazoling, antazoline,and pheniramimane.
 20. A topical ophthalmic composition comprising about0.01 to about 5% of an azalide antibiotic, an ophthalmically acceptablecarrier, and an additional medicament selected from the group consistingof antibiotics, antivirals, antifungals, anesthetics, anti-inflammatoryagents, and anti-allergic agents, wherein said topical ophthalmiccomposition has an osmotic pressure of from 10 to 400 mOsM and whereinsaid composition does not contain constituents that are physiologicallyor ophthalmically harmful to the eye.
 21. The composition according toclaim 20, wherein said composition is fluid; said azalide antibiotic iscontained in an amount of from about 0.01 to 2.0%; and said additionalmedicament is contained in an amount of from about 0.01 to 5.0%.
 22. Thecomposition according to claim 21, wherein said ophthalmicallyacceptable carrier is water or an aqueous solution and said additionalmedicament is selected from the group consisting of amikacin,gentamycin, tobramycin, streptomycin, netilmycin, kanamycinciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin,levofloxacin, enoxacin, sulfonamides, polymyxin, chloramphenicol,neomycin, paramomomycin, colistimethate, bacitracin, vancomycin,tetracyclines, rifampins, cycloserine, beta-lactams, cephalosporins,amphotericins, fluconazole, flucytosine, natamycin, miconazole,ketoconazole, corticosteroids, diclofenac, flurbiprofen, ketorolac,suprofen, comolyn, lodoxamide, levocabastin, naphazoling, antazoline,and pheniramimane.
 23. A process for treating an eye, comprising:topically applying an azalide antibiotic to an eye of a non-human animalin an amount effective to treat infection in a tissue of the eye,wherein said topically applying comprises supplying a depot of acomposition containing said azalide antibiotic on the eye.
 24. Theprocess according to claim 23, wherein said non-human animal is amammal.
 25. The process according to claim 23, wherein said mammal isselected from the group consisting of cows, sheep, horses, pigs, goats,rabbits, dogs, and cats.
 26. The process according to claim 23, whereinsaid depot is an aqueous polymeric suspension of said azalideantibiotic.
 27. The process according to claim 26, wherein said aqueouspolymeric suspension further comprises an additional medicament.
 28. Theprocess according to claim 27, wherein said additional medicament isselected from the group consisting of amikacin, gentamycin, tobramycin,streptomycin, netilmycin, kanamycin ciprofloxacin, norfloxacin,ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, enoxacin,sulfonamides, polymyxin, chloramphenicol, neomycin, paramomomycin,colistimethate, bacitracin, vancomycin, tetracyclines, rifampins,cycloserine, beta-lactams, cephalosporins, amphotericins, fluconazole,flucytosine, natamycin, miconazole, ketoconazole, corticosteroids,diclofenac, flurbiprofen, ketorolac, suprofen, comolyn, lodoxamide,levocabastin, naphazoling, antazoline, and pheniramimane.
 29. Theprocess according to claim 23, wherein said depot is a compositionselected from the group consisting of an aqueous suspensions, ointments,and inserts.
 30. The process according to claim 29, wherein said depotremains for at least 30 minutes after administration.
 31. The processaccording to claim 30, therein said depot remains for at least 4 hoursafter administration.
 32. The process according to claim 23, whereinsaid composition further comprises an additional medicament.
 33. Theprocess according to claim 32, wherein said additional medicament isselected from the group consisting of antibiotics, antivirals,antifungals, anesthetics, anti-inflammatory agents, and anti-allergicagents.
 34. The process according to claim 23, wherein said eye issuffering from at least one condition selected from the group consistingof conjunctivitis, ophthalmic neonatorum, trachoma, corneal ulcers,keratitis, keratoconjunctivitis, endophthalmitis, infectious uveitis andcombinations thereof, and said amount of said azalide antibiotic istherapeutically effective to treat said condition.
 35. The processaccording to claim 23, wherein said azalide antibiotic is a compound offormula (I):

wherein R¹ and R² each independently represent a hydrogen atom or methylgroup.
 36. The process according to claim 35, wherein said azalideantibiotic is azithromycin.
 37. The process according to claim 23,wherein said applying provides a therapeutically effective concentrationof azalide antibiotic within a tissue of the eye for at least 8 hours.38. The process according to claim 37, wherein said applying provides atherapeutically effective concentration of azalide antibiotic within atissue of the eye for at least 12 hours.
 39. The process according toclaim 38, wherein said applying provides a therapeutically effectiveconcentration of azalide antibiotic within a tissue of the eye for atleast 18 hours.
 40. The process according to claim 1, wherein the amountof said azalide antibiotic is at least about 5.0%.
 41. The processaccording to claim 1, wherein the amount of said azalide antibiotic isfrom about 0.1 to about 5.0%.
 42. The composition according to claim 20,wherein said composition is fluid; said azalide antibiotic is containedin an amount from at least about 5.0%, and said additional medicament iscontained in an amount of from about 0.01 to 5.0%.
 43. The compositionaccording to claim 20, wherein said composition is fluid; said azalideantibiotic is contained in an amount from about 0.1 to about 5.0%, andsaid additional medicament is contained in an amount of from about 0.001to 5.0%.
 44. A topical ophthalmic composition comprising an aqueouspolymeric suspension comprising water, from about 0.1 to about 5.0% ofan azalide antibiotic, and 0.1 to 10% of a polymeric suspending agent,wherein said topical ophthalmic composition has an osmotic pressure offrom 10 to 400 mOsM and wherein said composition does not containconstituents that are physiologically or ophthalmically harmful to theeye and said topical ophthalmic composition is in the form of a depotwhich is capable of sustained release of said azalide antibiotic. 45.The composition according to claim 20, wherein said azalide antibioticis azithromycin.